While the roles of cysteine as an antioxidant and in cell signaling are widely appreciated, only recently has it been recognized that methionine, like cysteine, functions as an antioxidant and as a key component of a system for regulation of cellular metabolism. The efficiency of methionine as an antioxidant or as a component of signaling systems depends on its ready interconversion between the reduced form (methionine) and the oxidized form (methionine sulfoxide). Methionine sulfoxide reductase catalyzes the reduction of methionine sulfoxide back to methionine. The major focus of our research in the last year continues to be the identification of proteins that interact with methionine sulfoxide reductase A in vivo. Despite concerted effort with a variety of techniques, we have not yet identified validated interacting proteins. Because of the importance of this issue, it will continue to be the focus of our research in the next reporting year.We will also focus on studies aimed at elucidating the roles of myristoylation. Overexpression of cytosolic, myristoylated reductase protects the heart from ischemia-perfusion mediated damage, although we have not yet elucidated the mechanism of protection. We are now also investigating the effects of deletion of all four of the known mammalian methionine sulfoxide reductases. Another major focus is to elucidate the mechanism by which alpha-synuclein forms covalent oligomers. Our on-going collaboration with the laboratory of Ad Bax has yielded an important advance that was published this year. The first metabolite of dopamine, DOPAL, was previously shown to be neurotoxic. David Goldstein has proposed the catecholaldehyde hypothesis that posits DOPAL as the molecule that initiates oligomeriation of synuclein. We reported that an initial derivative of synuclein is not the expected Schiff base with a protein lysine, but rather a novel catechol derivative, dicatechol pyrrole lysine or DCPL. Its formation from 2 DOPAL and a lysine residue is an oxidative modification of synuclein. We are now exploring how this modified synuclein could initiate oligomerization.